Type 1 diabetes (T1DM) is a chronic autoimmune disorder with a complex genetic susceptibility component; however, only about 10% of cases have a family history. Thus, a thorough understanding of the genetic factors that control susceptibility is crucial to prediction of, and subsequent intervention in, disease in the general population. The highest risk genetic marker identified to date (the HLA-DR3/DR4-DQB1*0302 genotype) only predicts an approximately 1 in 15 risk of disease in Caucasians, as compared to the general population risk of about 1 in 300. HLA genetic risk is even less well understood in non-Caucasian groups, and the spectrum of non-HLA genetic risk factors for all groups is just beginning to be elucidated. The autoimmune process that results in clinical onset of type 1 diabetes begins months to years before diagnosis and has complex etiology. Measurement of autoantibodies directed against insulin, glutamic acid decarboxylase (GAD65), and the tyrosine phosphatase-like protein IA-2 can give useful information about the progression of autoimmunity; however, these assays are not practical at the population level. In addition, autoantibodies are variable among prediabetic individuals and new-onset patients. Some ethnic groups, particularly African- Americans, exhibit clinical disease which differs from that in Caucasians; thus, thorough understanding of the genetics of true type 1 diabetes should aid in the diagnostic distinction of different forms of diabetes. This proposal aims to use a unique set of resources, which include state-of-the-art genotyping technology and access to sample sets from numerous ethnic groups as well as to the ethnically-diverse pediatric patient population at Children's Hospital Oakland, to study the genetic basis of susceptibility to type 1 diabetes. Specifically, we will analyze polymorphisms in known and novel candidate genetic susceptibility loci in large, family-based sample sets as well as in case-control studies. We will collect a multi-ethnic, "Bay Area" T1DM patient cohort, beginning with patients from Children's Hospital Oakland, and analyze candidate susceptibility loci, selected based on our prior studies. These experiments are expected to generate data that will help elucidate the multiple genetic factors that contribute to T1DM susceptibility.